Penciclovir for the treatment of zoster associated pain

ABSTRACT

A method for the treatment of ZAP, in particular PHN, in mammals, including humans, which method comprises administering to the mammal in need of such treatment, an effective amount of penciclovir or famciclovir, or a pharmaceutically acceptable salt thereof.

This application is a continuation in part application of U.S. Ser. No.08/624,466, filed May 15, 1998, now U.S. Pat. No. 5,866,581 which is aCPA, filed Jun. 20, 1996 and which is the §371 national stage entry ofPCT/GB94/02156, filed Oct. 4, 1994; and of U.S. Ser. No. 08/663,249,filed Jun. 18, 1996 which is the §371 national stage entry ofPCT/EP94/04163, filed Dec. 14, 1994.

FIELD OF THE INVENTION

This invention relates to the treatment of zoster associated pain, inparticular post-herpetic neuralgia, and to the use of compounds in thepreparation of a medicament for use in the treatment of this condition.

BACKGROUND OF THE INVENTION

EP-A-141927 (Beecham Group p.l.c.) discloses penciclovir, the compoundof formula (A): ##STR1## and salts, phosphate esters and acylderivatives thereof, as antiviral agents. The sodium salt hydrate ofpenciclovir is disclosed in EP-A-216459 (Beecham Group p.l.c.).Penciclovir and its antiviral activity is also disclosed in AbstractP.V11-5 p.193 of `Abstracts of 14th Int. Congress of Microbiology`,Manchester, England Sep. 7-13 1986 (Boyd et. al.).

Orally active bioprecursors of the compound of formula (A) are offormula (B): ##STR2## and salts and derivatives thereof as defined underformula (A); wherein X is C₁₋₆ alkoxy, NH₂ or hydrogen. The compounds offormula (B) wherein X is C₁₋₆ alkoxy or NH₂ are disclosed in EP-A-141927and the compounds of formula (B) wherein X is hydrogen, disclosed inEP-A-182024 (Beecham Group p.l.c.) are preferred prodrugs. Aparticularly preferred example of a compound of formula (B) is thatwherein X is hydrogen and wherein the two OH groups are in the form ofthe acetyl derivative, described in Example 2 of EP-A-182024,hereinafter referred to as famciclovir.

The compounds of formula (A) and (B) and salts and derivatives thereofhave been described as useful in the treatment of infections caused byherpes viruses, such as herpes simplex type 1, herpes simplex type 2,varicella-zoster and Epstein-Barr viruses.

Zoster associated pain (ZAP) is considered to consist of the painassociated with zoster infection and includes the acute phase pain andpost-herpetic neuralgia (PHN), which is by far the most commoncomplication of herpes zoster infection and one of the most intractablepain disorders (Strommen et al, Pharmacotherapy, 1988; 8:52-68).Patients who develop PHN suffer from a debilitating and oftenintractable pain which can persist for months or even years. Althoughrare in patients under 50 years of age, the frequency of PHN risessteeply with increasing age.

There is currently no proven therapy for preventing PHN. The pain is dueto injury of the nervous system and therefore seldom responds toanalgesia used to treat pain associated with tissue damage. Hence, thereis a need for therapy which alleviates or shortens the duration ofpost-herpetic neuralgia.

SUMMARY OF THE INVENTION

The present invention is to the use of Compounds of Formulae (A) and (B)as described herein, preferably famciclovir or penciclovir, for thetreatment, including prophylaxis, of zoster associated pain, inparticular post-herpatic neuralgia.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows Kaplan-Meier Plots of Time to Loss of PostherpeticNeuralgia, All Patients.

FIG. 2 shows Kaplan-Meier Plots of Time to Loss of PostherpeticNeuralgia, In Patients greater than or equal to 50 years of age.

DETAILED DESCRIPTION OF THE INVENTION

It has now been discovered that the above compounds are particularlyeffective in reducing the duration of ZAP, and in particular PHN, whengiven to the patient during the acute infection.

Accordingly, the present invention provides a method of treatment of ZAPin humans, which method comprises the administration to the human inneed of such treatment, an effective amount of a compound of formula(A): ##STR3## or a bioprecursor, or a pharmaceutically acceptable salt,phosphate ester and/or acyl derivative of either of the foregoing.

The present invention also provides a method for the treatment of PHN inhumans, which method comprises the administration to the human in needof such treatment, an effective amount of a compound of formula (A):##STR4## or a bioprecursor, or a pharmaceutically acceptable salt,phosphate ester and/or acyl derivative of either of the foregoing.

The term `acyl derivative` is used herein to include any derivative ofthe compounds of formula (A) in which one or more acyl groups arepresent. Such derivatives are included as bioprecursors of the compoundsof formula (A) in addition to those derivatives which are per sebiologically active.

The compound of formula (A) may be in one of the forms disclosed inEP-A-216459 (Beecham Group p.l.c.).

Examples of bioprecursors, pharmaceutically acceptable salts andderivatives are as described in the aforementioned European Patentreferences, the subject matter of which are incorporated herein byreference.

A particular compound of formula (B) of interest is9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine, known asfamciclovir (FCV), the well-absorbed oral form of penciclovir (PCV).

The compound of formula (A), bioprecursors, salts and derivatives may beprepared as described in the aforementioned European Patent references.

When used herein, `treatment` includes prophylaxis as appropriate.

The compound, in particular, famciclovir, may be administered by theoral route to humans and may be compounded in the form of syrup, tabletsor capsule. When in the form of a tablet, any pharmaceutical carriersuitable for formulating such solid compositions may be used, forexample magnesium stearate, starch, lactose, glucose, rice, flour andchalk. The compound may also be in the form of an ingestible capsule,for example of gelatin, to contain the compound, or in the form of asyrup, a solution or a suspension. Suitable liquid pharmaceuticalcarriers include ethyl alcohol, glycerine, saline and water to whichflavouring or colouring agents may be added to form syrups. Sustainedrelease formulations, for example tablets containing an enteric coating,are also envisaged.

For parenteral administration, fluid unit dose forms are preparedcontaining the compound and a sterile vehicle. The compound depending onthe vehicle and the concentration, can be either suspended or dissolved.Parenteral solutions are normally prepared by dissolving the compound ina vehicle and filter sterilising before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, preservatives and buffering agents are also dissolved inthe vehicle. To enhance the stability, the composition can be frozenafter filling into the vial and the water removed under vacuum.

Parenteral suspensions are prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilised by exposure to ethylene oxide before suspendingin the sterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound of the invention.

Preferred parenteral formulations include aqueous formulations usingsterile water or normal saline, at a pH of around 7.4 or greater, inparticular, containing penciclovir sodium salt hydrate.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned.

A suitable dosage unit might contain from 50 mg to 1 g of activeingredient, for example 100 to 500 mg. Such doses may be administered 1to 4 times a day or more usually 2 or 3 times a day. The effective doseof compound will, in general, be in the range of from 0.2 to 40 mg perkilogram of body weight per day or, more usually, 10 to 20 mg/kg perday. in the case of famciclovir, the dosage unit would be 250 mg, 500 mgor 750 mg, preferably 250 mg or 500 mg.

The treatment is preferably carried out as soon as possible aftersymptoms appear usually within 72 hours, preferably within 48 hours ofrash onset.

The treatment period is usually 7 days.

The treatment is particularly effective in the case of patients ofgreater than 50 years of age, and efficacy would be expected to bedemonstrated further in patients greater than 60 years of age,especially patients of greater than 70 years of age.

The present invention also provides the use of a compound of formula (A)or a bioprecursor, or a pharmaceutically acceptable salt, phosphateester and/or acyl derivative of either of the foregoing, in thepreparation of a medicament for use in the treatment of ZAP, and inparticular the treatment of PHN. Such treatment may be carried out inthe manner as hereinbefore described.

The present invention further provides a pharmaceutical composition foruse in the treatment of ZAP, and in particular the treatment of PHN,which comprises an effective amount of a compound of formula (A) or abioprecursor, or a pharmaceutically acceptable salt, phosphate esterand/or acyl derivative of either of the foregoing, and apharmaceutically acceptable carrier. Such compositions may be preparedin the manner as hereinafter described.

It is noted that Huff et al, Journal of Medical Virology, Supplement1:93-96 (1993) and Crooks et al, Scand J Infect--Suppl. 78:000--000,1991 describe the effect of acyclovir in ZAP.

The compound of formula (A) and its prodrugs show a synergisticantiviral effect in conjunction with interferons; and treatment usingcombination products comprising these two components for sequential orconcomitant administration, by the same or different routes, aretherefore within the ambit of the present invention. Such products aredescribed in EP-A-271270 (Beecham Group p.l.c.).

The following clinical data illustrate the invention.

Clinical Data:

Study 1 is described in Degreef et al, `International Journal ofMicrobial Agents, Volume 4, No. 4 (1994), pp 241-246.

A prospective, randomized, double-blind study (study 2) was conducted tocompare FCV dosed at 500 mg and 750 mg tid for 7 days with placebo inthe treatment of uncomplicated herpes zoster. 419 immunocompetentpatients, aged ≧18 years whose zoster rash had been present for ≦72hours were enrolled. Patients were assessed for lesion condition andpain pre-therapy, daily during week 1, daily until full crusting duringweek 2 and then weekly until all crust had been lost. Both FCV doseswere equally effective and significantly reduced the duration of VZVrecovery from zoster lesions and the time to healing of zoster lesionscompared with the placebo-treated group. In addition, a statisticallysignificant decrease in the duration of acute phase pain was detectedfor famciclovir-treated patients presenting with severe rash whencompared with placebo. The effect of famciclovir on PHN (defined as painat or after healing) was evaluated by assessing pain at 5 monthly visitsafter healing. The duration of PHN for all age groups was significantlyreduced from 128 days to 62 and 55 days following treatment with FCV 500mg and 750 mg, respectively. There were no significant differences inthe safety profiles between famciclovir and placebo. "The median time toloss of pain from enrollment (i.e. time to loss of ZAP) was 21 days and27 days for famciclovir doses of 500 mg and 750 mg respectively comparedwith 30 days for placebo. In conclusion, this study demonstrates thatfamciclovir dosed tid is an effective and well tolerated treatment forpatients with acute herpes zoster infection, significantly decreasingthe time to cutaneous lesion resolution and the duration of painmeasured both as PHN and as ZAP.

The table below summarises the results in ZAP from clinical studies withfamciclovir.

    ______________________________________                                        Endpoint                     FCV  FCV  FCV                                    (Study/Population)                                                                         Sub-group                                                                              ACV    250  500  750  PCB                               ______________________________________                                        TLZAP (Study 1/EE)                                                                         ≧50.sup.1                                                                       60     49   28   29   --                                TLZAP (Study 1/EE)                                                                         <48 hrs.sup.2                                                                          69     12*  17*  28*  --                                TLZAP (Study 1/EE)                                                                         <48/≧50.sup.3                                                                   69     28*.sup.1                                                                          56*.sup.2                                                                          29   --                                TLZAP (Study 2/EE)                                                                         <48 hrs.sup.2                                                                          --     --   26*  28*  64                                TLZAP (Study 2/EE)                                                                         ≧50.sup.1                                                                       --     --   28*  57*  76                                ______________________________________                                         .sup.1 = Patients aged 50 years or more treated within 72 hours               .sup.2 = Patients of all ages treated within 48 hours of rash onset           .sup.3 = Patients aged 50 years or more who were treated within 48 hours      of rash onset                                                                 .sup.*1 = Significant by Wilcoxon test                                        .sup.*2 = Significant by Log Rank Test                                        ITT = Intention to treat population                                           EE = Efficacy evaluable population                                            ACV = Acyclovir 800 mg five times daily for seven days                        PCB = Placebo treatment                                                       TLZAP = Time to loss of ZAP (time to loss of pain from enrolment)        

The invention is also illustrated by the following clinical data andpaper submitted for publication, entitled `Famciclovir for the treatmentof Acute Disease and Postherpetic Neuralgia` (ref--Tyring et al Abstract1540 of the 32nd Interscience Conference on Antimicrobial Agents andChemotherapy. New Orleans. American Society of Microbiology, 1993.)

Clinical Data:

A prospective, randomized, double-blind study was conducted to compareFCV dosed at 500 mg and 750 mg tid for 7 days with placebo in thetreatment of uncomplicated herpes zoster. 419 immunocompetent patients,aged ≧18 years whose zoster rash had been present for ≦72 hours wereenrolled. Patients were assessed for lesion condition and painpre-therapy, daily during week 1, daily until fill crusting during week2 and then weekly until all crust had been lost. Both FCV doses wereequally effective and significantly reduced the duration of VZV recoveryfrom zoster lesions and the time to healing of zoster lesions comparedwith the placebo-treated group. In addition, a statistically significantdecrease in the duration of acute phase pain was detected forfamciclovir-treated patients presenting with severe rash when comparedwith placebo. The effect of famciclovir on PHN (defined as pain at orafter healing) was evaluated by assessing pain at 5 monthly visits afterhealing. The duration of PHN for all age groups was significantlyreduced from 128 days to 62 and 55 days following treatment with FCV 500mg and 750 mg, respectively. There were no significant differences inthe safety profiles between famciclovir and placebo. In conclusion, thisstudy demonstrates that famciclovir dosed tid is an effective and welltolerated treatment for patients with acute herpes zoster infection,significantly decreasing the time to cutaneous lesion resolution and theduration of PHN.

The median times to loss of pain following healing in the above studywere compared with those seen in a second study (not placebo controlled)for all patients and in patients ≧50 years of age, to confirm that thespeed of pain resolutions were of the same order.

    ______________________________________                                                        FCV     FCV     FCV                                           Study Group     250 mg  500 mg  750 mg                                                                              Placebo                                 ______________________________________                                        first All       56      51      38                                            second                                                                              All               63      61    119                                     first ≧50 yrs                                                                          56      55      43                                            second                                                                              ≧50 yrs    63      63    163                                     ______________________________________                                    

These findings therefore further support the conclusions from theplacebo-controlled study that famciclovir provides a significantclinical benefit in shortening the duration of post-herpetic neuralgia.

One objective of this study was to document the effects of treatmentwith famciclovir on both the acute signs and symptoms of herpes zosterand postherpetic neuralgia.

Design: A randomized, double-blind, placebo-controlled, multicentertrial.

Setting: Thirty-six centers in the United States, Canada, and Australia.

Patients: Adults (419) with uncomplicated herpes zoster.

Intervention: Patients were randomized within 72 hours after rash onsetto receive famciclovir 500 mg, famciclovir 750 mg, or placebo threetimes daily for seven days.

Measurements: Lesions were assessed daily for up to 14 days until fullcrusting and then weekly until healing. Viral cultures were obtaineddaily while vesicles were present. Pain was assessed at each visit atwhich lesion assessments were made and then monthly for five monthsfollowing healing. Safety was assessed for the duration of the study.

Results. Famciclovir was well tolerated, with a safety profilecomparable with that of placebo. Famciclovir significantly acceleratedlesion healing and reduced the duration of viral shedding. Mostimportantly, patients treated with famciclovir had a significantly morerapid resolution of postherpetic neuralgia (˜2-fold faster) whencompared with placebo recipients, resulting in about a two monthreduction in the median duration of postherpetic neuralgia.

Conclusions. Oral famciclovir 500 mg or 750 mg given three times dailyfor seven days is an effective and well tolerated treatment for herpeszoster and significantly decreases the duration of the most debilitatingcomplication, postherpetic neuralgia.

Herpes zoster (shingles) occurs in 20% of the population and theincidence of the disease increases (three to four times) in the elderly(Gelb LD., Curr Opin Infect Dis. 1989; 2:256-61). The characteristiczoster rash is often accompanied by significant pain, dysesthesias, andskin hypersensitivity. The unmet challenge in the management of patientswith acute zoster is the amelioration of chronic pain. In many patientspain is lost once the affected area of skin returns to normal. However,some patients continue to experience pain long after healing and this iscommonly referred to as postherpetic neuralgia. Postherpetic neuralgiais by far the most common complication of herpes zoster infection and isone of the most intractable pain disorders (Portenoy et al. Ann Neurol.1986; 20:651-64, and Loeser JD. Pain. 1986; 25:149-64). The incidence ofpostherpetic neuralgia rises sharply with increasing age (Strommen etal., Pharmacotherapy. 1989; 8:52-68, and Demoragas et al., ArchDermatol. 1957; 75:193-6); nearly half of patients over 60 years of agewill suffer from this complication (Portenoy et al. Ann Neurol. 1986;20:651-64, and, Demoragas et al., Supra). Postherpetic neuralgia inolder patients is also more severe and persists longer than in youngerpatients (Loeser, J., Supra), and is clearly the most distressingcomponent of the disease process for both the patient and the physician.Although for many years acyclovir has been the only oral antiviral agentapproved for the treatment of patients with acute herpes zosterinfections, whether it has an effect on postherpetic neuralgia remainscontroversial (Wood et al., Am J Med. 1988; 85 (Suppl 2A):79-83; Huff etal. Am J Med. 1988; 85 (Suppl 2A):84-9; McKendricket al., Br Med J.1989; 298:431; Huff et al. J Med Virol. 1993; 1(Suppl 1):93-6; and Woodet al., New Engl J Med. 1994; 330:896-900).

Famciclovir is the well absorbed (77% bioavailable) (Pue et al.,Antiviral Chem Chemother. 1993; 4 (Suppl):47-55) oral form ofpenciclovir, a new antiviral agent with activity againstvaricella-zoster virus (VZV), herpes simplex virus (HSV) types 1 and 2,and Epstein-Barr virus (Boyd et al., Antimicrob Agents Chemother. 1987;31:1238-1242; Boyd et al., Antiviral Res. 1988; 9:146; Boyd et al.,Antiviral Chem Chemother. 1993; 4(Suppl):3-11; and Bacon et al.,Antiviral Chem Chemother. 1993; 4(Suppl):25-36). The in vitro potency ofboth penciclovir and acyclovir are dependent on the host cell and assaymethod used, but are generally comparable (Boyd et al., Antiviral ChemChemother. 1993; 4(Suppl):3-11; Bacon et al., Antiviral Chem Chemother.1993; 4(Suppl):25-36; DeClerq E. Antimicrob Agents Chemother. 1982;21:661-3).

The 50% plaque inhibitory concentrations (IC₅₀) in VZV-infected humanlung fibroblasts were 4.0±1.5 mcg/mL and 4.0±1.1 mcg/mL for penciclovirand acyclovir, respectively (Boyd et al., Antiviral Chem Chemother.1993; 4(Suppl):3-11). A potentially clinically important characteristicof penciclovir-triphosphate (PCV-TP) is that it persists invirus-infected host cells longer than acyclovir-triphosphate (ACV-TP)(Earnshaw et al., Antimicrob Agents Chemother. 1992; 36:2747-57). ForVZV-infected cells, the intracellular half-life of PCV-TP is 9.1 hours,in contrast to 0.8 hours for ACV-TP (Earnshaw et al., Antimicrob AgentsChemother. 1992; 36:2747-57; Standring-Cox et al., Abstract In: Programand Abstracts of the 7th International Conference on Antiviral Research.Charleston, S.C.; 1994:11). Thus, PCV-TP has the potential to continueto inhibit viral replication even if serum concentrations are below theinhibitory level.

Consistent oral bioavailability linked to a favorable intracellularhalf-life of PCV-TP in VZV-infected cells suggested that famciclovircould offer clinically important advantages in the management of herpeszoster infections over currently available therapy: a reduced totaldaily dose and a reduced dosing frequency. Also, there was theexpectation that more complete cover of antiviral activity throughoutthe dosing period could lead to improved clinical efficacy, especiallywith regard to postherpetic neuralgia. As a result, a study was designedto examine the effects of famciclovir on acute herpes zoster andpostherpetic neuralgia.

Methods

Study Design

This study was a randomized, double-blind, placebo-controlled,multicenter trial to assess the efficacy and safety of famciclovir 500mg or 750 mg versus placebo, given three times daily for seven days inthe treatment of patients with uncomplicated acute herpes zosterinfection.

Patients ≧18 years of age with clinically diagnosed uncomplicated herpeszoster infection based on clinical judgement who gave written informedconsent were eligible for study entry. Exclusion criteria includedpatients with zoster rash that had been present for >72 hours;complications of herpes zoster (eg, ocular or visceral involvement,disseminated zoster); presence of crusts at enrollment; patients withother serious underlying disease (eg, immunocompromised and/orHIV-infected individuals); or pregnant or lactating females.

Patients were prohibited from receiving any concomitant antiviral orimmunomodifying therapy and any topical medication which would beapplied to zoster lesions during the course of the study.

Patient Assessments

Patients were instructed to return to the clinic for lesion and painevaluations each of the seven therapy days and every day for the nextseven days following therapy. Patients with lesions that were fullycrusted by day 7 were examined every other day of the week followingtherapy. After day 14, weekly visits were required of all patients untilall lesions had lost their crusts. Patients were assessed for thepresence of postherpetic neuralgia at monthly intervals followinghealing for an additional five months.

The number of papules, vesicles, ulcers, and crusts within the primarydermatome was recorded as none, mild (<25 lesions), moderate (25-50lesions), or severe (>50 lesions). A specimen for viral culture wastaken at baseline and daily thereafter while vesicles were present.Patients were asked to rate the intensity of their pain on a scale ofnone, mild, moderate, or severe.

Adverse events were assessed at each visit according to time of onset,duration, severity, and investigator defined relationship to studymedication. Blood samples were obtained for assessment of chemistry andhematology and urine samples were obtained for dipstick analysis priorto study medication initiation and at the end of therapy visit.

Statistical Analysis

Efficacy endpoints were analyzed by standard survival methods. Analysesemployed the Cox proportional-hazards regression model (Cox DR, J RoyalStat Soc, Series B. 1972; 34:187-220). Time-dependent covariates weremodelled to evaluate the proportional hazards assumption and a modelincluding the main effects of treatment was employed to examineefficacy. Statistical conclusions were based on the significance ofestimated hazard ratios. These were constructed such that values largerthan one indicated a faster rate of event occurrence infamciclovir-treated patients than placebo. Two comparisons were made foreach endpoint: famciclovir 500 mg versus placebo and famciclovir 750 mgversus placebo. In addition, Kaplan-Meier estimates of the cumulativeproportion of patients achieving an event were employed to graphicallyillustrate the trial results. Proportion data were analyzed by means ofFisher's exact test (2-tailed).

The primary efficacy variable was time to full crusting. Secondaryvariables included duration of viral shedding; time to loss of vesicles,ulcers, crusts, and acute pain; and duration of postherpetic neuralgia(ie, time to loss of pain after healing). Healing was defined as thefirst visit at which a patient had no papules, vesicles, ulcers, orcrusts, and did not develop them at any later visit. Similarly, time toloss of a parameter was the time to complete cessation of that parameterwith no further report at any later date. Duration of viral shedding wasmeasured as the number of days from first dose of study medication tothe last positive culture.

The pre-study enrolment objective was 300 patients (100 per group). Thesample provided 80% power to detect a significant difference fromplacebo, assuming a true hazard ratio of 1.5 and exponential time tofull crusting (or time to event). Data from both the intention-to-treat(patients receiving at least one dose of study medication) andefficacy-evaluable (patients in compliance with the protocol)populations were analyzed. As the results of both analyses weregenerally comparable, in the current report, data are presented for theintention-to-treat population, unless otherwise specified. Prospectivelydefined subgroups with respect to age, duration of rash at enrolment,and severity of rash at enrolment were also examined. The safetyanalysis included all patients who had received at least one dose ofstudy medication. Each analysis included all patients providinginformation for the respective endpoint. That is, for example, theanalysis for time to loss of crusts included all patients who presentedwith crusts during the study.

Results

Demographics

Characteristics of all randomized patients (n=419) are shown in Table 1,including gender, age, duration of rash, location of rash, severity ofrash, and severity of pain. Approximately half of the patients werefemale. Mean age was 50 years. Over half of the patients had severe rashat enrolment and more than 60% of the patients had moderate or severezoster pain at enrolment.

Dermatological Assessment

Famciclovir treatment significantly accelerated lesion healing comparedwith placebo, as demonstrated by shorter times to full crusting, loss ofvesicles, loss of ulcers and loss of crusts. In general, the analysesfor both the intention-to-treat and the efficacy-evaluable populationswere similar and are presented in Table 2.

As noted above, full crusting occurred at a faster rate in patients whoreceived famciclovir compared with those who received placebo. In theintention-to-treat and efficacy-evaluable analyses, the hazard ratiosindicate a 1.3-1.5-fold faster time to full crusting for both thefamciclovir 500 mg group (hazard ratio: intention-to-treat=1.3;efficacy-evaluable=1.5) and the famciclovir 750 mg group (hazard ratio:intention-to-treat=1.4; efficacy-evaluable=1.5). Statisticallysignificant differences were detected for the famciclovir 500 mgrecipients in the efficacy-evaluable analysis (p=0.0245) and for thefamciclovir 750 mg recipients in the intention-to-treat and efficacyevaluable analyses (p=0.0228 and 0.0162, respectively).

Virological Assessment

Famciclovir significantly reduced the duration of viral sheddingcompared with placebo (p=0.0001). At baseline, 58%, 67%, and 70% ofpatients in the famciclovir 500 mg, famciclovir 750 mg, and placebogroups, respectively, had positive cultures for VZV. The proportion ofpatients who had stopped shedding virus after one day of treatment wasapproximately 60% for the famciclovir groups, compared with only 40% inthe placebo group.

Acute Pain Assessment

The median times to loss of acute phase pain were 20, 21, and 22 daysfor the famciclovir 500 mg, famciclovir 750 mg, and placebo groups,respectively. Hazard ratios were 1.2 for the famciclovir 500 mg groupand 1.1 for the famciclovir 750 mg group. Although there were nostatistically significant differences between the treatment groups inthe intention-to-treat population, in the efficacy-evaluable population,patients receiving famciclovir 500 mg lost pain significantly fasterthan placebo recipients (p=0.0176).

In addition, patients with severe rash (>50 lesions) at enrolment lostpain faster in both the famciclovir 500 mg (intention-to-treat: hazardratio=1.9; p=0.0028; efficacy-evaluable: hazard ratio=2.9; p=0.0001) andfamciclovir 750 mg (intention-to-treat: hazard ratio=1.3; p=0.2143;efficacy-evaluable: hazard ratio=2.0; p=0.0136) groups. The median daysto loss of pain for the famciclovir 500 mg, famciclovir 750 mg, andplacebo groups were 20, 27, and 30 days, respectively, in theintention-to-treat population and 20, 27, and 53 days, respectively, inthe efficacy-evaluable population. No consistent trends were noted forpatients presenting with mild or moderate rash at enrolment.

Postherpetic Neuralgia Assessment

Although there was a comparable proportion of patients who had painfollowing healing in all treatment groups (52%, 57%, 50% for famciclovir500 mg, famciclovir 750 mg, and placebo, respectively), both of thefamciclovir doses significantly reduced the duration of postherpeticneuralgia in the overall study population (FIG. 1). Hazard ratios were1.7 and 1.9 for famciclovir 500 mg and 750 mg, respectively, indicatingan almost two-fold reduction in time to postherpetic neuralgiaresolution compared with placebo; the reduction in duration ofpostherpetic neuralgia was statistically significant for both doses offamciclovir (p=0.0202 and 0.0050, respectively). Almost 90% percent ofthe patients analyzed for loss of postherpetic neuralgia had painassessments up to month 5. Median days to loss of postherpetic neuralgiawere 63, 61, and 119 days for the famciclovir 500 mg, famciclovir 750mg, and placebo groups, respectively.

In the subgroup of patients most likely to experience postherpeticneuralgia, i.e., those ≧50 years of age, postherpetic neuralgia resolved2.6-times faster in famciclovir recipients than in placebo recipients(p=0.0044 and p=0.0030, for famciclovir 500 mg and 750 mg, respectively;FIG. 2). Median days to loss of postherpetic neuralgia in these olderpatients were 63, 63, and 163 days for the famciclovir 500 mg,famciclovir 750 mg, and placebo groups, respectively, representing areduction in median time of almost 3.5 months for famciclovirrecipients. Significant benefit was not detected for the subgroup ofpatients <50 years of age.

Safety

Famciclovir was well tolerated, with a safety profile similar to that ofplacebo. The adverse event reported most frequently by the famciclovir500 mg, famciclovir 750 mg, and placebo recipients was headache (23.2%,22.2% and 17.8%, respectively) followed by nausea (12.3%, 12.6%, and11.6%, respectively). For events indicated by the investigator asrelated to study medication (related, possibly related, unknown or whereassessment was missing), once again, the most common adverse events inthe famciclovir 500 mg, famciclovir 750 mg and placebo groups wereheadache (8.0%, 8.1%, and 6.8%, respectively) and nausea (5.1%, 3.0%,and 8.2%, respectively). Famciclovir was not associated withabnormalities in hematology, liver function, clinical chemistry, orurinalysis parameters.

Discussion

Famciclovir given three times daily for seven days demonstratedsignificant reductions in the acute signs and symptoms of herpes zosterand the duration of viral shedding. Most striking was that the time tocessation of postherpetic neuralgia was significantly reduced inpatients who received famciclovir. Famciclovir was well tolerated, withan adverse event incidence comparable with that of placebo. No doseresponse relationship in efficacy or safety was apparent between the twofamciclovir doses.

For many years, acyclovir given 800 mg five times daily for seven to tendays has been the only oral antiviral agent approved for treatment ofacute herpes zoster. Its effectiveness in lessening the acute signs andsymptoms of herpes zoster has been established (Wood et al., Am J Med.1988; 85 (Suppl 2A):79-83; Huff et al. Am J Med. 1988; 85 (Suppl2A):84-9; McKendrick et al., Br Med J. 1986; 293:1529-32; Wood et al.,Infection. 1987; 15(Suppl 1):S9-13; and Sasadeusz et al., Derm Clinics.1993; 11:171-85), but "the effects of acyclovir on postherpeticneuralgia are less clear cut." (Wood et al., New Engl J Med. 1994;330:896-900).

Postherpetic neuralgia is a common severe complication of herpes zoster.In the largest acyclovir zoster trial (McKendricket al., Br Med J. 1989;298:431), no difference was shown between acyclovir and placebo ineither the incidence or the duration of postherpetic neuralgia, despiteenrolling only those patients most at risk of developing postherpeticneuralgia (eg, elderly). However, in two smaller trials (Huff et al. AmJ Med. 1988; 85 (Suppl 2A):84-9; Morton et al., NZ Med J. 1989;102:93-5) which enrolled both young and elderly patients in about equalproportions, some effects were seen during the first three months, butnot during months 4 to 6. When one of these studies was re-analyzed(Huff et al. J Med Virol. 1993; 1(Suppl 1):93-6), a significant effectwas seen on all zoster-associated pain (ie, continuum of pain fromenrolment into study until complete cessation), but postherpeticneuralgia was not addressed.

Additionally, a recent study evaluating acyclovir administered for 7 or21 days with or without concomitant prednisolone for the treatment ofacute herpes zoster revealed that although acute pain was reduced inpatients treated with concomitant prednisolone or 21 days of acyclovircompared with those who had received 7 days of acyclovir treatmentalone, neither the frequency of zoster-associated pain nor the time tocomplete cessation of pain was affected by the 14 additional days ofacyclovir treatment or by concomitant prednisolone therapy (Wood et al.,New Engl J Med. 1994; 330:896-900). No information on the duration ofpostherpetic neuralgia was reported from that study. Also, as this studydid not include a placebo control, no conclusion can be drawn regardingthe effect of acyclovir on postherpetic neuralgia.

Postherpetic neuralgia has been defined in relationship to acute zosteronset (Wood et al., Am J Med. 1988; 85 (Suppl 2A):79-83; Huff et al. AmJ Med. 1988; 85 (Suppl 2A):84-9; McKendricket al., Br Med J. 1989;298:431; and Morton et al., NZ Med J. 1989; 102:93-5), at time pointsranging from one to six months after zoster rash appears, and inrelationship to healing of zoster lesions (Cobo, et al. Ophthalmology.1986; 93(6):763-70; and Watson et al., Arch Neurol. 1986; 43:836-40), aswas done in the current study. Since the definition of postherpeticneuralgia varies between studies, comparability of patient populationsmay be shown by examining the prevalence of pain in the placebo-treatedgroups persisting six months after zoster rash onset. In the currentstudy, 18.5% of the placebo recipients reported pain six months afterrash onset; this value is in agreement with the prevalence of painreported by placebo recipients in other published studies (Wood et al.,Am J Med. 1988; 85 (Suppl 2A):79-83; McKendricket al., Br Med J. 1989;298:431; and Morton et al., NZ Med J. 1989; 102:93-5).

In this study, famciclovir clearly demonstrated a significant reductionin the duration of postherpetic neuralgia in comparison with placebo.Important features of the current study include prospectively definedpostherpetic neuralgia, the duration of follow-up (almost 90% ofpatients in the postherpetic neuralgia analysis were assessed fivemonths after healing), and reliance on rigorous statistical methodologyto evaluate the duration of postherpetic neuralgia. The present reportsummarizes postherpetic neuralgia over the entire follow-up period (fivemonths after healing) in a single statistic (ie, the hazard ratio).Additionally, the loss of pain was identified as the time at which thepatients reported no zoster related pain and, most importantly, theywere continued in the study and never reported pain again for theremainder of the study period. Thus, the value of two for an estimatedhazard ratio, indicates that the event of interest occurs twice asrapidly in patients receiving famciclovir than in controls. Patientsreceiving famciclovir during acute zoster lost postherpetic neuralgiaalmost two times faster than those receiving placebo (500 mg: hazardratio=1.7, p=0.0202; 750 mg: hazard ratio=1.9, p=0.0050). In olderpatients (≧50 years of age), who are more at risk and in whompostherpetic neuralgia persists longer, those who were treated withfamciclovir during acute zoster lost pain 2.6-times faster than thosewho received placebo (500 mg: p=0.0044; 750 mg: p=0.0030), resulting ina 3.5-month reduction in median duration of postherpetic neuralgia.

Oral famciclovir 500 mg or 750 mg administered three times daily forseven days during acute zoster offers a significant benefit to patientswith herpes zoster by providing a well tolerated convenient dosageregimen, effective relief of acute zoster signs and symptoms, andshortening the duration of postherpetic neuralgia.

                  TABLE 1                                                         ______________________________________                                        Patient Characteristics at Study Enrollment                                             Famciclovir                                                                             Famciclovir                                                         500 mg    750 mg    Placebo                                         ______________________________________                                        No. of Patients                                                                           138         135       146                                         % Female/Male                                                                             45.7/54.3   48.9/51.1 47.3/52.7                                   Mean Age (years)                                                                          50.1        49.5      49.1                                        <50 years (%)                                                                             49.3        48.9      52.1                                        ≧50 years (%)                                                                      50.7        51.1      47.9                                        Duration of Rash (%)                                                          <48 hours   47.8        56.3      49.3                                        48-72 hours 51.5*       43.7      50.7                                        Location of Rash (%)                                                          Thoracic    50.0        56.3      54.8                                        Cervical    25.4        18.5      26.0                                        Lumbar      14.5        13.3      13.7                                        Cranial     5.1         7.4       4.1                                         Sacral      5.1         4.4       1.4                                         Severity of Rash (%)                                                          No lesions  --          --        0.7                                         Mild        21.0        25.9      23.3                                        Moderate    22.5        20.7      24.7                                        Severe      56.5        53.3      51.4                                        Severity of Pain (%)                                                          None        5.8         5.9       8.2                                         Mild        24.1        28.9      33.6                                        Moderate    36.5        34.1      30.8                                        Severe      32.8        31.1      27.4                                        ______________________________________                                         *One patient (0.7%) enrolled at 77 hours after rash onset.               

                  TABLE 2                                                         ______________________________________                                        Cutaneous Lesion Resolution*                                                          Famciclovir 500 mg                                                                       Famciclovir 750 mg                                                                         Placebo                                       ______________________________________                                        Time to                                                                       Full Crusting                                                                 N         119 (91)     120 (92)     133 (101)                                 Median [days]                                                                           5 (6)        6 (6)        7 (7)                                     Hazard ratio                                                                            1.3 (1.5)    1.4 (1.5)                                              95% C.I.  1.0-1.7 (1.1-2.0)                                                                          1.0-1.9 (1.1-2.1)                                      p value.sup.†                                                                    0.0995 (0.0245)                                                                            0.0228 (0.0162)                                        Time to                                                                       Loss of Vesicles                                                              N         133 (104)    131 (103)    143 (110)                                 Median [days]                                                                           5 (5)        5 (5)        6 (6)                                     Hazard ratio                                                                            1.4 (1.6)    1.7 (2.0)                                              95% C.I.  1.1-1.9 (1.2-2.2)                                                                          1.3-2.2 (1.4-2.7)                                      p value.sup.†                                                                    0.0129 (0.0024)                                                                            0.0004 (0.0001)                                        Time to                                                                       Loss of Ulcers                                                                N         72 (55)      73 (59)      89 (70)                                   Median [days]                                                                           7 (7)        7 (7)        9 (10)                                    Hazard ratio                                                                            1.6 (1.7)    1.6 (1.7)                                              95% C.I.  1.1-2.2 (1.2-2.5)                                                                          1.1-2.2 (1.2-2.5)                                      p value.sup.†                                                                    0.0119 (0.0064)                                                                            0.0087 (0.0065)                                        Time to                                                                       Loss of Crusts                                                                N         129 (103)    126 (101)    142 (112)                                 Median [days]                                                                           19 (19)      20 (20)      21 (21)                                   Hazard ratio                                                                            1.3 (1.5)    1.2 (1.2)                                              95% C.I.  1.0-1.7 (1.1-2.0)                                                                          0.9-1.6 (0.9-1.6)                                      p value.sup.†                                                                    0.0476.sup.‡  (0.0092)                                                          0.1926 (0.2185)                                        ______________________________________                                         *Analyses for the intentionto-treat and efficacyevaluable (displayed in       parentheses) populations;                                                     .sup.† Famciclovir dose compared with placebo;                         .sup.‡ Not statistically significant after adjusting for           multiple comparisons (Hochberg, Y., Biometika. 1988;75(4):800-2)         

What is claimed is:
 1. A method for the treatment of zoster associatedpain (ZAP) in a human in need thereof, which method comprisesadministering to said human, an effective amount of the compound9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine (famciclovir), or apharmaceutically acceptable salt thereof.
 2. A method according to claim1 wherein treatment is commenced within 72 hours of rash onset.
 3. Amethod according to claim 2 wherein treatment is commenced within 48hours of rash onset.
 4. A method according to claim 1 where thetreatment period is 7 days.
 5. A method according to claim 1 wherein thetreatment is carried out on patients of greater than 50 years of age. 6.A method according to claim 5 wherein the treatment is carried out onpatients of greater than 60 years of age.
 7. A method according to claim6 wherein the treatment is carried out on patients of greater than 70years of age.
 8. A method according to claim 1 wherein famciclovir isadministered at a dose of 250 mg, 500 mg or 750 mg twice or three timesa day.
 9. A method according to claim 8 wherein famciclovir isadministered at a dose of 250 mg three times a day.
 10. A methodaccording to claim 8 wherein famciclovir is administered at a dose of500 mg three times a day.
 11. A method according to claim 8 whereinfamciclovir is administered at a dose of 500 mg twice a day.
 12. Amethod according to claim 8 wherein famciclovir is administered at adose of 750 mg once a day.
 13. A method for the prophylatic treatment ofpost-herpetic neuralgia (PHN) in a human in need thereof, which methodcomprises administering to said human, an effective amount of thecompound 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine(famciclovir), or a pharmaceutically acceptable salt thereof.
 14. Amethod according to claim 13 wherein the treatment is commenced within72 hours of rash onset.
 15. A method according to claim 14 wherein thetreatment is commenced within 48 hours of rash onset.
 16. A methodaccording to claim 13 where the treatment period is 7 days.
 17. A methodaccording to claim 13 wherein the treatment is carried out on patientsof greater than 50 years of age.
 18. A method according to claim 17wherein the treatment is carried out on patients of greater than 60years of age.
 19. A method according to claim 18 wherein the treatmentis carried out on patients of greater than 70 years of age.
 20. A methodaccording to claim 13 wherein famciclovir is administered at a dose of250 mg, 500 mg or 750 mg once, twice or three times a day.
 21. A methodaccording to claim 20 wherein famciclovir is administered at a dose of250 mg three times a day.
 22. A method according to claim 20 whereinfamciclovir is administered at a dose of 500 mg three times a day.
 23. Amethod according to claim 20 wherein famciclovir is administered at adose of 500 mg twice a day.
 24. A method according to claim 20 whereinfamciclovir is administered at a dose of 750 mg once a day.
 25. A methodfor the treatment of zoster associated pain (ZAP) in a human in needthereof, which method comprises administering to said human, aneffective amount of the compound9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (penciclovir), or apharmaceutically acceptable salt thereof.
 26. A method according toclaim 25 wherein the treatment is commenced within 72 hours of rashonset.
 27. A method according to claim 26 wherein the treatment iscommenced within 48 hours of rash onset.
 28. A method according to claim25 where the treatment period is 7 days.
 29. A method according to claim25 wherein the treatment is carried out on patients of greater than 50years of age.
 30. A method according to claim 29 wherein the treatmentis carried out on patients of greater than 60 years of age.
 31. A methodaccording to claim 30 wherein the treatment is carried out on patientsof greater than 70 years of age.
 32. A method according to claim 25wherein penciclovir is administered topically.
 33. A method according toclaim 25 wherein the compound is the sodium salt of penciclovir.
 34. Amethod according to claim 25 wherein the compound is administeredparenterally.
 35. A method for the prophylatic treatment ofpost-herpetic neuralgia (PHN) in a human in need thereof, which methodcomprises administering to said human, an effective amount of thecompound 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (penciclovir), ora pharmaceutically acceptable salt thereof.
 36. A method according toclaim 35 wherein the treatment is commenced within 72 hours of rashonset.
 37. A method according to claim 36 wherein the treatment iscommenced within 48 hours of rash onset.
 38. A method according to claim35 where the treatment period is 7 days.
 39. A method according to claim35 wherein the treatment is carried out on patients of greater than 50years of age.
 40. A method according to claim 39 wherein the treatmentis carried out on patients of greater than 60 years of age.
 41. A methodaccording to claim 40 wherein the treatment is carried out on patientsof greater than 70 years of age.
 42. A method according to claim 35wherein the compound is administered parenterally.